Combination treatment for migraine and other pain

ABSTRACT

Disclosed herein are methods of treating pain, such as migraine, comprising administering meloxicam and rizatriptan to a human being suffering from pain, such as migraine. For migraine, these methods may be particularly useful when the meloxicam and rizatriptan are administered while the human being is suffering from an acute attack of migraine pain or migraine aura. In some embodiments, the combination of meloxicam and rizatriptan may be administered in a manner that results in a Tmax of meloxicam of 3 hours or less.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of PCT/US18/32162, filed May10, 2018, which is continuation-in-part of PCT/US18/12433, filed Jan. 4,2018; PCT/US18/32162 also claims benefit of U.S. Provisional ApplicationNos. 62/536,466, filed Jul. 25, 2017, 62/526,884, filed Jun. 29, 2017;this application also claims benefit of U.S. Provisional ApplicationNos. 62/802,198, filed Feb. 6, 2019, 62/803,756, filed Feb. 11, 2019,62/835,613, filed Apr. 18, 2019, and 62/846,311, filed on May 10, 2019;all of which are incorporated by reference herein in their entirety.

BACKGROUND

There continues to be a need for therapies with improved efficacy intreating migraine and related conditions.

SUMMARY

Disclosed herein are methods of treating pain, such as migraine,comprising administering meloxicam and rizatriptan to a human beingsuffering from pain, such as migraine. For migraine, these methods maybe particularly useful when the meloxicam and rizatriptan areadministered while the human being is suffering from an acute attack ofmigraine pain or migraine aura. In some embodiments, about 8-13 mg ofrizatriptan is administered to the human being. In some embodiments, thecombination of meloxicam and rizatriptan (e.g. 8-13 mg of rizatriptan)may be administered in a manner that results in a T_(max) of meloxicamof 3 hours or less, 2 hours or less, 110 minutes or less, and/or anAUC₀₋₂₄ of meloxicam of about 30-50 μg·hr/mL.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of meloxicam plasma concentration at various timepoints over the first 24 hours for an embodiment of a dosage formdescribed herein and a commercially available meloxicam dosage form.

DETAILED DESCRIPTION

A combination of rizatriptan and meloxicam (referred to herein forconvenience as a “subject combination”) may be used to treat a varietyof pain conditions.

Rizatriptan has the structure as shown below.

Meloxicam has the structure:

Meloxicam exhibits anti-inflammatory, analgesic, and antipyreticactivities. The meloxicam mechanism of action may be related to theinhibition of prostaglandin synthetase (cyclo-oxygenase, COX) which isinvolved in the initial steps of the arachidonic acid cascade, resultingin the reduced formation of prostaglandins, thromboxanes andprostacylin.

Unless otherwise indicated, any reference to a compound herein, such asmeloxicam or rizatriptan, by structure, name, or any other means,includes pharmaceutically acceptable salts, alternate solid forms, suchas polymorphs, solvates, hydrates, enantiomers, tautomers,deuterium-modified forms, or any other chemical species, such asprecursors, prodrugs, or any other chemical species that may rapidlyconvert to a compound described herein under conditions in which thecompounds are used as described herein.

A subject combination may be given enterally including, but not limitedto, oral, sublingual, or rectal delivery, or parenterally including, butnot limited to, intravenous, intramuscular, intranasal, or subcutaneousdelivery. In some embodiments, both meloxicam and rizatriptan areadministered orally. In some embodiments, meloxicam is administeredintravenously and rizatriptan is administered orally. In someembodiments, meloxicam is administered intramuscularly and rizatriptanis administered orally.

Normally, the combination of meloxicam and rizatriptan is administeredso that the human being receives the meloxicam and rizatriptan within ashort period of time with respect to one another. For example, themeloxicam and rizatriptan may be administered within about 2 hours,within about 1 hour, within about 30 minutes, within about 20 minutes,within about 15 minutes, within about 10 minutes, within about 5minutes, or within about 1 minute of one another. In some embodiments,the meloxicam and rizatriptan are administered simultaneously, which forthe purpose of this disclosure includes administration within about 5minutes. In some embodiments, the meloxicam and rizatriptan areadministered in a single dosage form.

The term “treating” or “treatment” broadly includes any kind oftreatment activity, including the diagnosis, cure, mitigation, orprevention of disease in man or other animals, or any activity thatotherwise affects the structure or any function of the body of man orother animals.

A subject combination may be used to treat, or provide relief of, anytype of pain including, but not limited to, migraine and other types ofheadache, inflammatory pain, musculoskeletal pain, neuropathic pain,chronic pain, acute pain, localized pain, systemic pain, cancer-relatedpain, acute pain, pain due to injury, pain due to illness (e.g., fever),post-operative pain, etc. In some instances, pain relief may bepalliative, or pain relief may be provided independent of improvement ofthe disease or condition or the underlying cause of the disease orcondition. For example, although the underlying disease may not improve,or may continue to progress, an individual suffering from the diseasemay experience pain relief. In some embodiments, the pain affects amuscle, nerve, cartilage, bone, ligament, tendon, tendon sheaths,bursae, or joint.

Migraine is a headache disorder characterized by recurrent headachesthat may be moderate to severe. The headaches may affect one half of thehead, may be pulsating in nature, and may last from 2 to 72 hours.Associated symptoms may include nausea, vomiting, and sensitivity tolight (photophobia), sound (phonophobia), or smell. The pain can be madeworse by physical activity. Migraines may be associated with an aura,which may be a short period of visual disturbance which signals that theheadache will soon occur.

Administering a subject combination to a human being suffering frommigraine, such as an acute attack of migraine pain or aura, may quicklyresult in a reduction in a migraine symptom, such as pain, nausea,vomiting, photophobia, or phonophobia, such as at or within about 5minutes (intended as a shorthand for “at about 5 minutes, or withinabout 5 minutes”), at or within about 10 minutes, at or within about 30minutes, at or within about 1 hour, at or within about 90 minutes, at orwithin about 2 hours, at or within about 2.5 hours, or at or withinabout 3 hours. In some embodiments, a human being experiences areduction of, or complete relief from, pain, such as headache pain ormigraine pain, nausea, vomiting, photophobia, and/or phonophobia, at orwithin about 1 hour, at or within about 90 minutes, at or within about 2hours, at or within about 2.5 hours, or at or within about 3 hours. Insome embodiments, the relief experienced, is greater than would beexperienced by receiving the same amount of rizatriptan withoutmeloxicam. In some embodiments, the relief experienced, is greater thanwould be experienced by receiving the same amount of meloxicam withoutrizatriptan.

Observation of relief or reduction in a symptom at a specific period oftime, such as “at 2 hours,” is useful because it allows theeffectiveness of the treatment to be evaluated at a specific orconsistent time point, which facilitates comparison between patients.Observation of relief or reduction in a symptom within a specific periodof time, such as “within about 2 hours,” is useful because it isdesirable for relief or reduction of a symptom to occur as early aspossible, and specifying that relief occur within a specified time setsa guideline in which it is desirable that relief occur.

For some methods, administration of the subject combination may achievea reduction in migraine pain, nausea, vomiting, photophobia, orphonophobia that lasts at least about one hour, at least about twohours, at least about three hours, at least about four hours, at leastabout six hours, at least about eight hours, about 8-24 hours, about 24hours, or more than 24 hours.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater pain relief than thehuman being would have experienced two hours after receiving the sameamount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater painrelief than the human being would have experienced twenty-four hoursafter receiving the same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater pain relief than thehuman being would have experienced two hours after receiving the sameamount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater painrelief than the human being would have experienced twenty-four hoursafter receiving the same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from nauseathan the human being would have experienced two hours after receivingthe same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom nausea than the human being would have experienced twenty-fourhours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from nauseathan the human being would have experienced two hours after receivingthe same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom nausea than the human being would have experienced twenty-fourhours after receiving the same amount of rizatriptan without themeloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from vomitingthan the human being would have experienced two hours after receivingthe same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom vomiting than the human being would have experienced twenty-fourhours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from vomitingthan the human being would have experienced two hours after receivingthe same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom vomiting than the human being would have experienced twenty-fourhours after receiving the same amount of rizatriptan without themeloxicam. In some embodiments, the meloxicam and the rizatriptan areadministered simultaneously (e.g. in a single dosage form, such as asingle oral dosage form), and two hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom photophobia than the human being would have experienced two hoursafter receiving the same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom photophobia than the human being would have experienced twenty-fourhours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief fromphotophobia than the human being would have experienced two hours afterreceiving the same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom photophobia than the human being would have experienced twenty-fourhours after receiving the same amount of rizatriptan without themeloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief fromphonophobia than the human being would have experienced two hours afterreceiving the same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom phonophobia than the human being would have experienced twenty-fourhours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief fromphonophobia than the human being would have experienced two hours afterreceiving the same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom phonophobia than the human being would have experienced twenty-fourhours after receiving the same amount of rizatriptan without themeloxicam.

In some embodiments, the human being receiving the subject combinationhas a history of inadequate response to prior migraine treatments. Forexample, if the human being is asked whether he or she was pain-freewithin two hours of treatment for most attacks, and given the option ofanswering “never,” “rarely,” “less than half the time,” or “half thetime or more;” and the human being answers “never,” “rarely,” or “lessthan half the time,” then the human being has had an inadequate responseto the treatment. Similarly, if the human being is asked whether onedose of medication usually relieved the human being's headache and keptit away for at least 24 hours, and given the option of answering“never,” “rarely,” “less than half the time,” or “half the time ormore;” and the human being answers “never,” “rarely,” or “less than halfthe time,” then the human being has had an inadequate response to thetreatment.

In some embodiments, the human being receiving the subject combinationhas indicated that he or she was “never” pain-free within two hours oftreatment for most attacks. In some embodiments, the human beingreceiving the subject combination has indicated that he or she was“rarely” pain-free within two hours of treatment for most attacks. Insome embodiments, the human being receiving the subject combination hasindicated that he or she was pain-free within two hours of treatment formost attacks “less than half the time.”

In some embodiments, the human being receiving the subject combinationhas indicated that one dose of medication “never” relieved therespondent's headache and kept it away for at least 24 hours. In someembodiments, the human being receiving the subject combination hasindicated that one dose of medication “rarely” relieved the respondent'sheadache and kept it away for at least 24 hours. In some embodiments,the human being receiving the subject combination has indicated that onedose of medication relieved the respondent's headache and kept it awayfor at least 24 hours “less than half the time.”

In some methods, the subject combination may be administered to relieveinflammatory pain, including inflammatory musculoskeletal pain, pain dueto injury, arthritis pain, and complex regional pain syndrome. In otherembodiments, the inflammatory pain may be chronic or acute.

In some embodiments, the subject combination may be administered torelieve arthritis pain, or other signs and/or symptoms of arthritis.Arthritis refers to inflammatory joint diseases that can be associatedwith pain. Examples of arthritis include, but are not limited to,rheumatoid arthritis, juvenile rheumatoid arthritis (pauciarticular andpolyarticular course), osteoarthritis, erosive osteoarthritis,sero-negative (non-rheumatoid), arthropathies, non-articular rheumatism,peri-articular disorders, axial spondyloarthritis, transientosteoarthritis of the hip, vertebral crush fractures, arthritisassociated with osteoporosis, and neuropathic arthropathies includingCharcot's foot, axial spondyloarthritis including ankylosingspondylitis, and SAPHO syndrome. In other embodiments, the arthritispain may be chronic or acute. In some embodiments the subjectcombination may be administered to relief the signs and/or symptoms ofan arthritis including but not limited to osteoarthritis.

In some embodiments, the subject combination may be administered torelieve neuropathic pain, including diabetic peripheral neuropathy,post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies,phantom limb pain, sciatica, pudendal neuralgia, and central pain. Othercauses of neuropathic pain may include, but are not limited to,cancer-related pain, lumbar nerve root compression, spinal cord injury,post-stroke pain, central multiple sclerosis pain, HIV-associatedneuropathy, and radio-therapy or chemo-therapy associated neuropathy.The neuropathic pain may be chronic or acute.

For some methods, the subject combination may be administered to relievemusculoskeletal pain. Examples of musculoskeletal pain may include, butare not limited to, back pain, low back pain (e.g., lumbosacral pain),neck pain, infection, cramps, tendonitis, epidondylitis, carpal tunnelsyndrome, joint pain, fibromyalgia, pain due to injury, Tunnelsyndromes, pain associated with bone fractures, sprains, fibrousdysplasia, osteogenesis imperfecta, Paget's disease of bone, transientosteoporosis, and transient osteoporosis of the hip. In otherembodiments, the musculoskeletal pain may be chronic or acute.

For some methods, administration of the subject combination may achievea reduction in pain that lasts at least about one hour, at least abouttwo hours, at least about three hours, at least about four hours, atleast about six hours, at least about eight hours, about 8 to about 24hours, or about 24 hours. In other embodiments, administration of thesubject combination may achieve a reduction in pain that is observed atabout 10 minutes, at about 30 minutes, at about one hour, at about twohours, at about three hours, at about four hours, at about five hours,at about six hours, at or within about 5 minutes, at or within about 10minutes, at or within about 15 minutes, at or within about 20 minutes,at or within about 25 minutes, at or within about 30 minutes, at orwithin about 35 minutes, at or within about 40 minutes, at or withinabout 45 minutes, at or within about 50 minutes, or at or within about60 minutes, at two hours or less, at three hours or less, or other timeperiod bound by these ranges, after administration of the subjectcombination.

A human being that is treated for a disease or condition, such asmigraine, with a subject combination may be of any age. For example theperson may have an age of about 0.1-10 years, about 10-90 years, about20-80 years, about 30-75 years, about 40-70 years, about 1-16 years,about 80-95 years, about 18 years or more, about 20 years or more, about25 years or more, about 30 years or more, about 40 years or more, about45 years or more, about 50 years or more, about 55 years or more, about60 years or more, about 65 years or more, or any other age in a rangebounded by, or between, any of these values.

In some embodiments, a human being that is treated for a disease orcondition, such as migraine, with a subject combination has sufferedfrom the condition for at least 1 day, at least one week, at least 2weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3months, at least 6 months, at least 1 year, at least 5 years, at least10 years, at least 15 years, at least 20 years, at least 30 years, atleast 40 years, at least 50 years or any duration in a range bounded by,or between, any of these values.

In some embodiments, use of a cyclodextrin or a bicarbonate in a dosageform comprising the subject combination may improve the solubility ororal bioavailability (e.g. a higher C_(max) and/or higher AUC) ofmeloxicam in a subject (human or animal) by at least about 10%, at leastabout 20%, at least about 30%, at least about 40%, at least about 50%,at least about 60%, at least about 70%, at least about 80%, at leastabout 90%, up to about 100%, up to about 200%, or any amount in a rangebounded by, or between, any of these values as compared toadministration of meloxicam alone.

In some embodiments, use of a cyclodextrin or a bicarbonate used in thesubject combination may improve the solubility or oral bioavailability(e.g. a higher C_(max) and/or higher AUC) of rizatriptan in a subject(human or animal) by at least about 10%, at least about 20%, at leastabout 30%, at least about 40%, at least about 50%, at least about 60%,at least about 70%, at least about 80%, at least about 90%, up to about100%, up to about 200%, or any amount in a range bounded by, or between,any of these values as compared to administration of the rizatriptanalone.

In some embodiments, a dosage form used in the subject combination,including an oral, intravenous, or intramuscular dosage form, maycontain meloxicam in an amount of about 1-50 mg; about 1-10 mg; about1-5 mg; about 10-40 mg; about 1-35 mg; about 2-6 mg, about 3-7 mg, about4-8 mg, about 5-10 mg, about 7-12 mg, about 5-15 mg, about 10-20 mg,about 10-30 mg, about 18-22 mg, about 19-21 mg, about 15-25 mg, about20-30 mg, about 25-35 mg, about 30-40 mg, about 35-45 mg, about 40-50mg, about 1-25 mg; about 1-15 mg; about 5-20 mg; about 5 mg; about 7.5mg; about 10 mg; about 15 mg; about 20 mg; about 30 mg; or any amount ina range bounded by, or between, any of these values. For any amounts ofmeloxicam (or any other compound) described herein, salt forms ofmeloxicam (or another compound) may be present in the amounts recitedabove, or amounts that are molar equivalents to these amounts for thenon-salt form of meloxicam (or another compound). These doses may besafe for repeated administration, such as 1, 2, 3, or 4 times a day, ormay be repeated at an interval of about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 8 days, about 9days, about 10 days, about 11 days, about 12 days, about 13 days, about14 days, about 15 days, about 16 days, about 17 days, about 18 days,about 19 days, about 20 days, about 21 days, about 22 days, about 23days, about 24 days, about 25 days, about 26 days, about 27 days, about28 days, about 29 days, about 30 days, about 31 days, about 1-2 months,about 4 weeks, about 6 weeks, about 4-6 weeks, about 2-3 months, about3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about7-8 months, about 8-9 months, about 9-10 months, about 10-11 months,about 11-12 months, about 1-2 years, about 2 years, etc.

In some embodiments; a dosage form comprising the subject combinationmay contain rizatriptan in an amount of about 1-50 mg; about 1-10 mg;about 10-20 mg; about 20-30 mg; about 30-40 mg; or about 40-50 mg; about10-40 mg; about 1-35 mg; about 1-25 mg; about 1-15 mg; about 1-10 mg;about 5-20 mg; about 1-5 mg; about 2-6 mg; about 3-7 mg; about 4-8 mg;about 5-10 mg; about 6-11 mg; about 7-12 mg; about 8-13 mg; about 9-11mg; about 9-14 mg; about 10-15 mg; about 11-16 mg; about 12-17 mg; about13-18 mg; about 14-19 mg; about 15-20 mg; about 5-15 mg; about 0.5 mg;about 1 mg; about 1.5 mg; about 2 mg; about 2.5 mg; about 3 mg; about3.5 mg; about 4 mg; about 4.5 mg; about 5 mg; about 6 mg; about 7 mg;about 7.5 mg; about 8 mg, about 9 mg, about 10 mg; about 15 mg; about 20mg, about 25 mg, about 30 mg; or any amount in a range bounded by, orbetween, any of these values.

For acute migraines, the amount of meloxicam and/or rizatriptan in asingle dose, or the AUC of the meloxicam and/or rizatriptan associatedwith a single dose, is of particular interest. For example, after asingle dose, the symptoms may be relieved for an extended period oftime, such that, in the short term, repeated doses may not be needed.For more continuous conditions, including more chronic, continuous, orfrequent migraine symptoms, daily, weekly, or monthly doses may be ofparticular interest.

For any amounts of rizatriptan described herein, salt forms ofrizatriptan may be present in the amounts recited above, or amounts thatare molar equivalents to these amounts for the rizatriptan free base.For example, assuming that the molecular weight of rizatriptan free baseis 269.3 g/mol, 10 mg of rizatriptan is 37.1 mmol of rizatriptan. Thus,a molar equivalent of 10 mg of rizatriptan free base would be the massof 37.1 mmol of that salt form. For example, for the benzoate salt(mw=391.2 g/mol), the molar equivalent of 10 mg of the free base (or37.1 mmol), would be 14.5 mg. These doses may be safe for repeatedadministration, such as 1, 2, 3, or 4 times a day, or repeated at aninterval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8months, about 8-9 months, about 9-10 months, about 10-11 months, about11-12 months, etc.

For some dosage forms, a cyclodextrin (such as SBEβCD) may be present inan amount of about 1-200 mg; about 1-100 mg; about 25-175 mg; about50-150 mg; about 50-100 mg; about 50-200 mg; about 25-100 mg; about75-150 mg; about 100-175 mg; about 20-80 mg; about 25-50 mg; about60-100 mg; about 80-100 mg; about 100 mg; about 80-120 mg; about 100-120mg; about 100-140 mg; about 120-160 mg; about 140-180 mg; about 150-200mg, about 100-150 mg; about 30-90 mg; about 40-60 mg; about 40-80 mg;about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amount in a rangebounded by, or between, any of these values. A cyclodextrin may beeffective in decreasing T_(max) and/or increasing AUC of meloxicamand/or rizatriptan.

For some dosage forms, an inclusion complex of a drug (such as meloxicamor rizatriptan) and cyclodextrin is about 1-10%, about 5-20%, about5-15%, about 6-16%, about 7-17%, about 8-18%, about 9-19%, about 10-20%,about 15-30%, about 30-40%, about 40-50%, about 50-70%, or about 70-90%of the total weight of the dosage form, or any percentage in a rangebounded by any of these values.

Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) inamount of about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about200-800 mg; about 1-500 mg; about 1-200 mg; about 1400 mg; about 50-750mg; about 500-1000 mg; about 100-500 mg; about 100-300 mg; about500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about50-100 mg; about 250-750 mg; about 100-200 mg; about 200-300 mg; about300-400 mg; about 400-500 mg; about 410-510 mg; about 420-520 mg; about430-530 mg; about 440-540 mg; about 450-550 mg; about 460-560 mg; about470-570 mg; about 480-580 mg; about 490-590 mg; about 500-600 mg; about600-700 mg; about 700-800 mg; about 800-900 mg; about 900-1,000 mg;about 150-650 mg; about 350-850 mg; about 400 mg; about 450 mg; about500 mg, about 550 mg; about 600 mg; or any amount in a range bounded by,or between, any of these values.

A bicarbonate, such as sodium bicarbonate, may be at least about 10%, atleast about 15%, at least about 20%, about 20-40%, about 30-50%, about40-60%, about 50-70%, about 60-80%, or about 70-90%, or any percentagein a range bounded by any of these values, of the total weight of thedosage form.

In some embodiments, the daily dose of meloxicam, or the amount ofmeloxicam administered in a single day (either in one administration, orby two or more divided doses adding up to the daily dose) is about 2-5mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg,about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 2-45 mg,about 2-50 mg, about 2-55 mg, about 2-60 mg, about 2-65 mg, about 2-70mg, about 2-75 mg, about 3-8 mg, about 4-9 mg, about 5-10 mg, about 6-11mg, about 7-12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about11-16 mg, about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20mg, about 16-21 mg, about 17-22 mg, about 18-23 mg, about 19-24 mg,about 20-25 mg, about 21-26 mg, about 22-27 mg, about 23-28 mg, about24-29 mg, about 25-30 mg, about 26-31 mg, about 27-32 mg, about 28-33mg, about 29-34 mg, about 30-35 mg, about 31-36 mg, about 32-37 mg,about 33-38 mg, about 34-39 mg, about 35-40 mg, about 36-41 mg, about37-42 mg, about 38-43 mg, about 39-44 mg, about 40-45 mg, about 41-46mg, about 42-47 mg, about 43-48 mg, about 44-49 mg, about 45-50 mg,about 46-51 mg, about 47-52 mg, about 48-53 mg, about 49-54 mg, about50-55 mg, about 51-56 mg, about 52-57 mg, about 53-58 mg, about 54-59mg, about 55-60 mg, about 56-61 mg, about 57-62 mg, about 58-63 mg,about 59-64 mg, about 60-65 mg, about 61-66 mg, about 62-67 mg, about63-68 mg, about 64-69 mg, about 65-70 mg, about 66-71 mg, about 67-72mg, about 68-73 mg, about 69-74 mg, about 70-75 mg, or any amount in arange bounded by any of these values. The daily dose may be given as asingle dose, given once a day, or may be given in 2, 3, 4, or moredivided doses during a day.

In some embodiments, the weekly dose of meloxicam or the amount ofmeloxicam administered in a week (either in one administration, or bytwo or more divided doses adding up to the weekly dose) is about 1-1000mg; about 1-500 mg; about 10-250 mg; about 100-300 mg; about 10-100 mg;about 10-150 mg; about 10-300 mg; about 20-150 mg; about 20-60 mg; about30-70 mg; about 40-60 mg; about 50-70 mg; about 70-90 mg; about 90-110mg; about 80-450 mg; about 80-100 mg; about 90-110 mg; about 100420 mg;about 110430 mg; about 120-140 mg; about 130-150 mg; about 140-160 mg;about 150470 mg; about 160-180 mg; about 170-190 mg; about 180-200 mg;about 190-210 mg; about 200-220 mg; about 210-230 mg; about 220-240 mg;about 230-250 mg; about 240-260 mg; about 250-270 mg; about 260-280 mg;about 270-290 mg; about 280-300 mg; about 290-310 mg; about 300-320 mg;about 310-330 mg; about 320-340 mg; about 330-350 mg; about 340-360 mg;about 350-370 mg; about 360-380 mg; about 370-390 mg; about 380-400 mg;about 390-410 mg; about 400-420 mg; about 410-430 mg; about 420-440 mg;about 430-450 mg; about 50 mg; about 55 mg; about 100-150 mg; about30-100 mg; or any amount in a range bounded by, or between, any of thesevalues. The weekly dose may be given as a single dose, given once aweek, or may be given in 2, 3, 4, 5, 6, or 7 individual doses during aweek.

In some embodiments, the monthly dose of meloxicam (e.g., an oral dose),or a dose administered over a period of a month, is about 5000 mg orless; about 4000 mg or less; about 3000 mg or less; about 2000 mg orless; about 1000 mg or less; about 700 mg or less; about 600 mg or less;about 300-2400 mg; about 300-350 mg; about 310-360 mg; about 320-370 mg;about 330-380 mg; about 340-390 mg; about 350-400 mg; about 360-410 mg;about 370-420 mg; about 380-430 mg; about 390-440 mg; about 400-450 mg;about 410-460 mg; about 420-470 mg; about 430-480 mg; about 440-490 mg;about 450-500 mg; about 460-510 mg; about 470-520 mg; about 480-530 mg;about 490-540 mg; about 500-550 mg; about 510-560 mg; about 520-570 mg;about 530-580 mg; about 540-590 mg; about 550-600 mg; about 560-610 mg;about 570-620 mg; about 580-630 mg; about 590-640 mg; about 600-650 mg;about 610-660 mg; about 620-670 mg; about 630-680 mg; about 640-690 mg;about 650-700 mg; about 660-710 mg; about 670-720 mg; about 680-730 mg;about 690-740 mg; about 700-750 mg; about 710-760 mg; about 720-770 mg;about 730-780 mg; about 740-790 mg; about 750-800 mg; about 760-810 mg;about 770-820 mg; about 780-830 mg; about 790-840 mg; about 800-850 mg;about 810-860 mg; about 820-870 mg; about 830-880 mg; about 840-890 mg;about 850-900 mg; about 860-910 mg; about 870-920 mg; about 880-930 mg;about 890-940 mg; about 900-950 mg; about 910-960 mg; about 920-970 mg;about 930-980 mg; about 940-990 mg; about 950-1000 mg; about 960-1010mg; about 970-1020 mg; about 980-1030 mg; about 990-1040 mg; about1000-1050 mg; about 1010-1060 mg; about 1020-1070 mg; about 1030-1080mg; about 1040-1090 mg; about 1050-1100 mg; about 1060-1110 mg; about1070-1120 mg; about 1080-1130 mg; about 1090-1140 mg; about 1100-1150mg; about 1110-1160 mg; about 1120-1170 mg; about 1130-1180 mg; about1140-1190 mg; about 1150-1200 mg; about 1160-1210 mg; about 1170-1220mg; about 1180-1230 mg; about 1190-1240 mg; about 1200-1250 mg; about1210-1260 mg; about 1220-1270 mg; about 1230-1280 mg; about 1240-1290mg; about 1250-1300 mg; about 1260-1310 mg; about 1270-1320 mg; about1280-1330 mg; about 1290-1340 mg; about 1300-1350 mg; about 1310-1360mg; about 1320-1370 mg; about 1330-1380 mg; about 1340-1390 mg; about1350-1400 mg; about 1360-1410 mg; about 1370-1420 mg; about 1380-1430mg; about 1390-1440 mg; about 1400-1450 mg; about 1410-1460 mg; about1420-1470 mg; about 1430-1480 mg; about 1440-1490 mg; about 1450-1500mg; about 1460-1510 mg; about 1470-1520 mg; about 1480-1530 mg; about1490-1540 mg; about 1500-1550 mg; about 1510-1560 mg; about 1520-1570mg; about 1530-1580 mg; about 1540-1590 mg; about 1550-1600 mg; about1560-1610 mg; about 1570-1620 mg; about 1580-1630 mg; about 1590-1640mg; about 1600-1650 mg; about 1610-1660 mg; about 1620-1670 mg; about1630-1680 mg; about 1640-1690 mg; about 1650-1700 mg; about 1660-1710mg; about 1670-1720 mg; about 1680-1730 mg; about 1690-1740 mg; about1700-1750 mg; about 1710-1760 mg; about 1720-1770 mg; about 1730-1780mg; about 1740-1790 mg; about 1750-1800 mg; about 1760-1810 mg; about1770-1820 mg; about 1780-1830 mg; about 1790-1840 mg; about 1800-1850mg; about 1810-1860 mg; about 1820-1870 mg; about 1830-1880 mg; about1840-1890 mg; about 1850-1900 mg; about 1860-1910 mg; about 1870-1920mg; about 1880-1930 mg; about 1890-1940 mg; about 1900-1950 mg; about1910-1960 mg; about 1920-1970 mg; about 1930-1980 mg; about 1940-1990mg; about 1950-2000 mg; about 1960-2010 mg; about 1970-2020 mg; about1980-2030 mg; about 1990-2040 mg; about 2000-2050 mg; about 2010-2060mg; about 2020-2070 mg; about 2030-2080 mg; about 2040-2090 mg; about2050-2100 mg; about 2060-2110 mg; about 2070-2120 mg; about 2080-2130mg; about 2090-2140 mg; about 2100-2150 mg; about 2110-2160 mg; about2120-2170 mg; about 2130-2180 mg; about 2140-2190 mg; about 2150-2200mg; about 2160-2210 mg; about 2170-2220 mg; about 2180-2230 mg; about2190-2240 mg; about 2200-2250 mg; about 2210-2260 mg; about 2220-2270mg; about 2230-2280 mg; about 2240-2290 mg; about 2250-2300 mg; about2260-2310 mg; about 2270-2320 mg; about 2280-2330 mg; about 2290-2340mg; about 2300-2350 mg; about 2310-2360 mg; about 2320-2370 mg; about2330-2380 mg; about 2340-2390 mg; about 2350-2400 mg; about 1-4000 mg;about 1-1000 mg; about 10-1000 mg; about 50-1000 mg; about 10-600 mg;about 40-600 mg; about 50-600 mg; about 40-400 mg; about 50-200 mg;about 200-240 mg; about 240-280 mg; about 280-320 mg; about 320-360 mg;about 360-400 mg; about 400-450 mg; about 450-500 mg; about 500-600 mg;about 250-350 mg; about 100-600 mg; about 40-2000 mg; about 40-800 mg;about 100-900 mg; about 100-800 mg; about 40-1000 mg; about 50-1000 mg;about 100-1000 mg; or any monthly dose in a range bounded by, orbetween, any of these values.

A monthly dose of meloxicam may be given as a single dose, or as two ormore individual doses administered during the month. In someembodiments, the monthly dose is administered bi-weekly in 2 or 3divided doses. In some embodiments, the monthly dose is administeredweekly in 4 or 5 divided doses. In some embodiments, the monthly dose isadministered daily in 28 to 31 divided doses, or in 56 to 62 divideddoses or more. In some embodiments, the monthly dose is administered in5 to 15 individual doses during the month. The monthly dose may beadministered for only 1 month, or may be repeatedly administered for 2,3, 4, 5, 6, or more months.

In some embodiments, the daily dose of rizatriptan is about 0.5-100 mg,about 5-50 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about30-40 mg, about 40-50 mg, about 1-5 mg, about 1-6 mg, about 2-7 mg,about 3-8 mg, about 4-9 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg,about 8-13 mg, about 9-14 mg, about 10-15 mg, about 11-16 mg, about12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 16-21mg, about 17-22 mg, about 18-23 mg, about 19-24 mg, about 20-25 mg,about 21-26 mg, about 22-27 mg, about 23-28 mg, about 24-29 mg, about25-30 mg, about 26-31 mg, about 27-32 mg, about 28-33 mg, about 29-34mg, about 30-35 mg, about 31-36 mg, about 32-37 mg, about 33-38 mg,about 34-39 mg, about 35-40 mg, about 36-41 mg, about 37-42 mg, about38-43 mg, about 39-44 mg, about 40-45 mg, about 41-46 mg, about 42-47mg, about 43-48 mg, about 44-49 mg, about 45-50 mg, about 46-51 mg,about 47-52 mg, about 48-53 mg, about 49-54 mg, about 50-55 mg, or anyamount in a range bounded by any of these values. The daily dose may begiven as a single dose, given once a day, or may be given in 2, 3, 4, ormore divided doses during a day.

In some embodiments, the weekly dose of rizatriptan is about 14000 mg;about 10-400 mg, about 50-250 mg, about 1-500 mg; about 10-250 mg; about100-300 mg; about 10-100 mg; about 10-150 mg; about 10-300 mg; about20-150 mg; about 20-60 mg; about 30-70 mg; about 40-60 mg; about 50-70mg; about 70-90 mg; about 90-110 mg; about 50 mg; about 55 mg; about100-150 mg; about 30-100 mg; about 1-20 mg; about 1-10 mg; about 2-10mg; about 2-5 mg; about 540 mg; about 1-50 mg; about 10-60 mg; about20-70 mg; about 30-80 mg; how about 40-90 mg; about 50-100 mg; about60410 mg; about 70420 mg; about 80-130 mg; about 90-140 mg; about 100450mg; about 110-160 mg; about 120-170 mg; about 130-180 mg; about 140490mg; about 150-200 mg; about 160-210 mg; about 170-220 mg; about 180-230mg; about 190-240 mg; about 200-250 mg; about 210-260 mg; about 220-270mg; about 230-280 mg; about 240-290 mg; about 250-300 mg; about 260-310mg; about 270-320 mg; about 280-330 mg; about 290-340 mg; about 300-350mg; about 310-360 mg; about 320-370 mg; about 330-380 mg; about 340-390mg; about 350-400 mg; or any amount in a range bounded by, or between,any of these values. The weekly dose may be given as a single dose,given once a week, or may be given in 2, 3, 4, 5, 6, or 7 individualdoses during a week.

In some embodiments, the monthly dose of rizatriptan, or a total doseadministered within a period of a month, is about 5000 mg or less; about4000 mg or less; about 3000 mg or less; about 2000 mg or less; about1000 mg or less; about 700 mg or less; about 600 mg or less; about1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 50-1000 mg; about10-600 mg; about 40-600 mg; about 50-600 mg; about 150-2400 mg, about150-200 mg; about 160-210 mg; about 170-220 mg; about 180-230 mg; about190-240 mg; about 200-250 mg; about 210-260 mg; about 220-270 mg; about230-280 mg; about 240-290 mg; about 250-300 mg; about 260-310 mg; about270-320 mg; about 280-330 mg; about 290-340 mg; about 300-350 mg; about310-360 mg; about 320-370 mg; about 330-380 mg; about 340-390 mg; about350-400 mg; about 360-410 mg; about 370-420 mg; about 380-430 mg; about390-440 mg; about 400-450 mg; about 410-460 mg; about 420-470 mg; about430-480 mg; about 440-490 mg; about 450-500 mg; about 460-510 mg; about470-520 mg; about 480-530 mg; about 490-540 mg; about 500-550 mg; about510-560 mg; about 520-570 mg; about 530-580 mg; about 540-590 mg; about550-600 mg; about 560-610 mg; about 570-620 mg; about 580-630 mg; about590-640 mg; about 600-650 mg; about 610-660 mg; about 620-670 mg; about630-680 mg; about 640-690 mg; about 650-700 mg; about 660-710 mg; about670-720 mg; about 680-730 mg; about 690-740 mg; about 700-750 mg; about710-760 mg; about 720-770 mg; about 730-780 mg; about 740-790 mg; about750-800 mg; about 760-810 mg; about 770-820 mg; about 780-830 mg; about790-840 mg; about 800-850 mg; about 810-860 mg; about 820-870 mg; about830-880 mg; about 840-890 mg; about 850-900 mg; about 860-910 mg; about870-920 mg; about 880-930 mg; about 890-940 mg; about 900-950 mg; about910-960 mg; about 920-970 mg; about 930-980 mg; about 940-990 mg; about950-1000 mg; about 960-1010 mg; about 970-1020 mg; about 980-1030 mg;about 990-1040 mg; about 1000-1050 mg; about 1010-1060 mg; about1020-1070 mg; about 1030-1080 mg; about 1040-1090 mg; about 1050-1100mg; about 1060-1110 mg; about 1070-1120 mg; about 1080-1130 mg; about1090-1140 mg; about 1100-1150 mg; about 1110-1160 mg; about 1120-1170mg; about 1130-1180 mg; about 1140-1190 mg; about 1150-1200 mg; about1160-1210 mg; about 1170-1220 mg; about 1180-1230 mg; about 1190-1240mg; about 1200-1250 mg; about 1210-1260 mg; about 1220-1270 mg; about1230-1280 mg; about 1240-1290 mg; about 1250-1300 mg; about 1260-1310mg; about 1270-1320 mg; about 1280-1330 mg; about 1290-1340 mg; about1300-1350 mg; about 1310-1360 mg; about 1320-1370 mg; about 1330-1380mg; about 1340-1390 mg; about 1350-1400 mg; about 1360-1410 mg; about1370-1420 mg; about 1380-1430 mg; about 1390-1440 mg; about 1400-1450mg; about 1410-1460 mg; about 1420-1470 mg; about 1430-1480 mg; about1440-1490 mg; about 1450-1500 mg; about 1460-1510 mg; about 1470-1520mg; about 1480-1530 mg; about 1490-1540 mg; about 1500-1550 mg; about1510-1560 mg; about 1520-1570 mg; about 1530-1580 mg; about 1540-1590mg; about 1550-1600 mg; about 1560-1610 mg; about 1570-1620 mg; about1580-1630 mg; about 1590-1640 mg; about 1600-1650 mg; about 1610-1660mg; about 1620-1670 mg; about 1630-1680 mg; about 1640-1690 mg; about1650-1700 mg; about 1660-1710 mg; about 1670-1720 mg; about 1680-1730mg; about 1690-1740 mg; about 1700-1750 mg; about 1710-1760 mg; about1720-1770 mg; about 1730-1780 mg; about 1740-1790 mg; about 1750-1800mg; about 1760-1810 mg; about 1770-1820 mg; about 1780-1830 mg; about1790-1840 mg; about 1800-1850 mg; about 1810-1860 mg; about 1820-1870mg; about 1830-1880 mg; about 1840-1890 mg; about 1850-1900 mg; about1860-1910 mg; about 1870-1920 mg; about 1880-1930 mg; about 1890-1940mg; about 1900-1950 mg; about 1910-1960 mg; about 1920-1970 mg; about1930-1980 mg; about 1940-1990 mg; about 1950-2000 mg; about 1960-2010mg; about 1970-2020 mg; about 1980-2030 mg; about 1990-2040 mg; about2000-2050 mg; about 2010-2060 mg; about 2020-2070 mg; about 2030-2080mg; about 2040-2090 mg; about 2050-2100 mg; about 2060-2110 mg; about2070-2120 mg; about 2080-2130 mg; about 2090-2140 mg; about 2100-2150mg; about 2110-2160 mg; about 2120-2170 mg; about 2130-2180 mg; about2140-2190 mg; about 2150-2200 mg; about 2160-2210 mg; about 2170-2220mg; about 2180-2230 mg; about 2190-2240 mg; about 2200-2250 mg; about2210-2260 mg; about 2220-2270 mg; about 2230-2280 mg; about 2240-2290mg; about 2250-2300 mg; about 2260-2310 mg; about 2270-2320 mg; about2280-2330 mg; about 2290-2340 mg; about 2300-2350 mg; about 2310-2360mg; about 2320-2370 mg; about 2330-2380 mg; about 2340-2390 mg; about2350-2400 mg; about 40-400 mg; about 50-200 mg; about 200-240 mg; about240-280 mg; about 280-320 mg; about 320-360 mg; about 360-400 mg; about400-450 mg; about 450-500 mg; about 500-600 mg; about 250-350 mg; about100-600 mg; about 40-2000 mg; about 40-800 mg; about 100-900 mg; about100-800 mg; about 40-1000 mg; about 50-1000 mg; about 100-1000 mg; about10-80 mg; about 10-40 mg; about 20-30 mg; or any monthly dose in a rangebounded by, or between, any of these values. A monthly dose ofrizatriptan may be given as a single dose, or as two or more individualdoses administered during the month. In some embodiments, the monthlydose is administered bi-weekly in 2 or 3 divided doses. In someembodiments, the monthly dose is administered weekly in 4 or 5 divideddoses. In some embodiments, the monthly dose is administered daily in 28to 31 divided doses, or in 56 to 62 divided doses or more. In someembodiments, the monthly dose is administered in 5 to 15 individualdoses during the month. The monthly dose may be administered for only 1month, or may be repeatedly administered for 2, 3, 4, 5, 6, or moremonths.

In other embodiments, the subject combination may be administered weeklyfor about one, two, three, four, or more consecutive weeks, every otherweek or hi-weekly, or once every three weeks. This regimen may berepeated once weekly, twice in a month, three times in a month, oncemonthly, once every two months, once every three months, or as directedby a medical professional.

Any reference to T_(max), C_(max), AUC, or any other pharmacokineticparameter should be understood to include an average, mean, or medianvalue in human beings, such as human patients or human subjects.

The subject combination may be administered in an amount and mannerintended to target therapeutically effective plasma concentrations. Forexample, an area under the plasma concentration curve (AUC) ofmeloxicam, such as a median, mean, or average AUC of meloxicam in humanbeings, of about 1-150 μg·hr/mL may be targeted, such as about 10-30μg·hr/mL; about 20-40 μg·hr/mL; about 30-50 μg·hr/mL; about 40-60μg·hr/mL; about 50-70 μg·hr/mL; about 60-80 μg·hr/mL; about 70-90μg·hr/mL; about 80-100 μg·hr/mL; about 10-100 μg·hr/mL; about 50-150μg·hr/mL; about 25-125 μg·hr/mL; about 75-150 μg·hr/mL; about 20-50μg·hr/mL; about 40-70 μg·hr/mL; about 60-90 μg·hr/mL; about 80-110μg·hr/mL; about 100-130 μg·hr/mL; about 120-150 μg·hr/mL; about 100-150μg·hr/mL; about 20-30 μg·hr/mL; about 30-40 μg·hr/mL; about 40-50μg·hr/mL; about 50-60 μg·hr/mL; about 20-25 μg·hr/mL, about 25-30μg·hr/mL, about 30-35 μg·hr/mL, about 35-40 μg·hr/mL, about 40-45μg·hr/mL, about 45-50 μg·hr/mL, or any AUC in a range bounded by, orbetween, any of these values.

Unless otherwise indicated, the AUC refers to the AUC calculated to thelast measured concentration (AUC_(0-t)), such as, over a period of 6hours (AUC₀₋₆), over a period of 12 hours (AUC₀₋₁₂), over a period of 24hours (AUC₀₋₂₄), or extrapolated to infinity (AUC_(0-inf)).

In Example 1 below, the AUC₀₋₂₄ of meloxicam in human beings for an oraldosage form containing sodium bicarbonate and sulfobutyletherβ-cyclodextrin (SBEβCD) was about 27 μg·hr/mL. This dosage formcontained 15 mg of meloxicam.

The 15 mg IV and intramuscular doses also provide an AUC₀₋₂₄ ofmeloxicam in human beings that is about 27 μg·hr/mL. The AUC ofmeloxicam is believed to be approximately dose proportional. So for thisoral dosage form, or for an IV or intramuscular dosage form, a meloxicamdose of, for example, approximately 17 mg to about 30 mg would beexpected to result in an AUC₀₋₂₄ of meloxicam of about 30-50 μg·hr/mL.

For some acute pain conditions, such as migraine and other types ofheadache, the AUC for a short period after oral administration, such asan AUC measured over 6 hours (or AUC₀₋₆), may be of particular interest,e.g. for quick pain relief. For example, some dosage forms may result inan AUC₀₋₆ of meloxicam, such as a median, mean, or average AUC₀₋₆ ofmeloxicam in human beings, that is at least about 5 μg·hr/mL (or 5,000ng·hr/mL); at least about 6 μg·hr/mL (or 6,000 ng·hr/mL); at least about7 μg·hr/mL (or 7,000 ng·hr/mL); at least about 8 μg·hr/mL (or 8,000ng·hr/mL); at least about 9 μg·hr/mL (or 9,000 ng·hr/mL); about 6-10μg·hr/mL; about 7-11 μg·hr/mL; about 8-12 μg·hr/mL; about 9-13 μg·hr/mL;about 10-14 μg·hr/mL; or any AUC₀₋₆ in a range bounded by, or between,any of these values.

In some embodiments, the subject combination is administered in a mannerthat results in a C_(max) of meloxicam, such as a median, mean, oraverage C_(max) of meloxicam in human beings, of about 10-2500 ng/mL;about 100-2250 ng/mL; about 500-2000 ng/mL; about 1000-2500 ng/mL; about1000-2000 ng/mL; about 100-900 ng/mL; about 750-1500 ng/mL; about1250-2000 ng/mL; about 1500-2300 ng/mL; about 800-1200 ng/mL; about1900-2400 ng/mL; about 50-500 ng/mL; about 400-950 ng/mL; about 900-1500ng/mL; about 1100-2200 ng/mL; about 1300-1600 ng/mL; about 1200-1500ng/mL; about 1400-2100 ng/mL; about 1500-1900 ng/mL; about 1600-2100ng/mL; about 1700-2000 ng/mL; about 1900-2500 ng/mL; about 1500-1700ng/mL; about 1600-1800 ng/mL; about 1700-1900 ng/mL; about 1800-2000ng/mL; about 1900-2100 ng/mL; about 2000-2200 ng/mL; about 2100-2300ng/mL; about 2200-2400 ng/mL; about 2300-2500 ng/mL; about 2500-3000ng/mL; at least about 1400 ng/mL; at least about 1500 ng/mL; at leastabout 1600 ng/mL; at least about 1700 ng/mL; at least about 1800 ng/mL;at least about 1900 ng/mL; at least about 2000 ng/mL; at least about2100 ng/mL; at least about 2200 ng/mL; at least about 2300 ng/mL; atleast about 2400 ng/mL; at least about 2500 ng/mL; or any C_(max) in arange bounded by, or between, any of these values.

The methods described herein relate to administration of the subjectcombination in a human being in a manner that results in a relativelyshort T_(max), such as a T_(max) within about 10 minutes; within about20 minutes; within about 30 minutes; within about 40 minutes; withinabout 50 minutes; within about 60 minutes; within about 70 minutes;within about 80 minutes; within about 90 minutes; within about 100minutes; within about 110 minutes; within about 120 minutes; withinabout 180 minutes; about 10-30 minutes; about 20-40 minutes, about 30-50minutes, about 40-60 minutes; about 50-70 minutes; about 60-90 minutes;about 70-100 minutes; about 80-110 minutes; about 90-120 minutes; or anyT_(max) in a range bounded by, or between, any of these values afteradministration of the subject combination.

In some embodiments, the subject combination is administered in a mannersuch that a time to half-maximal plasma concentration of meloxicam, suchas a median, mean, or average time to half-maximal plasma concentrationin human beings, that is less than about 5 minutes; less than about 10minutes; less than about 15 minutes; less than about 20 minutes; lessthan about 25 minutes; less than about 30 minutes; less than about 35minutes; less than about 40 minutes; less than about 45 minutes; lessthan about 50 minutes; less than about 55 minutes; less than about 60minutes; less than about 90 minutes; about 5-15 minutes; about 10-20minutes, about 15-25 minutes, about 20-30 minutes; about 25-35 minutes;about 30-45 minutes; about 35-50 minutes; about 40-55 minutes; about45-60 minutes; about 0.5-5 hours; or any time in a range bounded by anyof these values.

For example, a method described herein may reduce the T_(max) ofrizatriptan, such as a median, mean, or average T_(max) of rizatriptanin human beings. In some embodiments, the method may include treating apatient to achieve the T_(max) of rizatriptan in the patient withinabout 60 minutes; within about 70 minutes; within about 80 minutes;within about 90 minutes; within about 100 minutes; within about 110minutes; within about 2 hours; within about 3 hours; within about 4hours; about 10-30 minutes; about 20-40 minutes; about 30-50 minutes;about 40-60 minutes; about 50-70 minutes; about 60-80 minutes; about70-90 minutes; about 0.1-1 hour; about 0.1-0.5 hours; about 0.5-1 hour;about 1-10 h; about 2-9 h; about 3-7 h; about 4-6 h; about 1-5 h; about2-7 h; about 3-8 h; about 4-9 h; about 1-4 h; about 2-5 h; about 3-6 h;about 4-7 h; about 5-8 h; about 6-9 h; about 7-10 h; or any T_(max) in arange bounded by, or between, any of these values after administrationof the subject combination.

The oral dosage form of Example 1 below gave a T_(max) of meloxicam ofapproximately 30 minutes. The T_(max) of intravenous meloxicam isapproximately 30 minutes for an infusion or 3 minutes for a bolus. TheT_(max) of intramuscular meloxicam is approximately 60-84 minutes.

In some embodiments, a subject combination may be administered in amanner that results in a plasma concentration of meloxicam, such as amedian, mean, or average plasma concentration of meloxicam in humanbeings, at 12 hours that is about 0.01-0.5 μg/mL; about 0.5-0.7 μg/mL;about 0.6-0.8 μg/mL; about 0.7-0.9 μg/mL; about 0.8-1 μg/mL; about0.01-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2 μg/mL; about 1.1-1.3μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL; about 1-1.5 μg/mL;about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about1.7-1.9 μg/mL; about 1.8-2 μg/mL; about 1.5-2 μg/mL; about 1.9-2.1μg/mL; about 2-2.2 μg/mL; about 2.1-2.3 μg/mL; about 2.2-2.4 μg/mL;about 2.3-2.5 μg/mL; about 2-2.5 μg/mL; about 2.4-2.6 μg/mL; about2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL; about 2.8-3μg/mL; about 2.5-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2 μg/mL; about3.1-3.3 μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL; about 3-3.5μg/mL; about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about 3.6-3.8 μg/mL;about 3.7-3.9 μg/mL; about 3.8-4 μg/mL; about 3.5-4 μg/mL; or any plasmaconcentration of meloxicam at 12 hours in a range bounded by, orbetween, any of these values.

In some embodiments, meloxicam is administered at a dose that results ina meloxicam average plasma level (such as a C_(ave), or average plasmalevel) of about 0.01-0.5 μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8μg/mL; about 0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.01-1 μg/mL; about0.9-1.1 μg/mL; about 1-1.2 μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4μg/mL; about 1.3-1.5 μg/mL; about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL;about 1.6-1.8 μg/mL; about 1.7-1.9 μg/mL; about 1.8-2 μg/mL; about 1-2μg/mL; about 0.01-3 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about2.1-2.3 μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2.4-2.6μg/mL; about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL;about 2.8-3 μg/mL; about 2-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL;about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about 3.6-3.8 μg/mL; about3.7-3.9 μg/mL; about 3.8-4 μg/mL; about 3-4 μg/mL; about 2-4 μg/mL;about 0.01-4 μg/mL; about 0.1-20 μg/mL; about 0.5-15 μg/mL; about 0.5-10μg/mL; about 5-15 μg/mL; about 10-20 μg/mL; about 7.5-15 μg/mL; about2-10 ug/m L; about 1-8 μg/mL; about 1-6 μg/mL; about 1-2 μg/mL; about0.5-3.5 μg/mL; about 0.5-7 ug/m L; about 12-20 μg/mL; about 8-12 μg/mL;about 1-4 μg/mL; about 4-7 μg/mL; about 7-11 μg/mL; about 11-15 μg/mL;about 15-19 μg/mL; about 16-20 μg/mL; or any meloxicam average plasmalevel in a range bounded by, or between, any of these values.

In some embodiments, a dosage form containing meloxicam, rizatriptan, orboth, may be formulated for oral administration, for example, with aninert diluent or with an edible carrier, or it may be enclosed in hardor soft shell gelatin capsules, compressed into tablets, or incorporateddirectly with the food of the diet. For oral therapeutic administration,the active compound may be incorporated with an excipient and used inthe form of ingestible tablets, buccal tablets, coated tablets, troches,capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers,patches, and the like.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the unit dosageform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoating, for instance, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially non-toxic inthe amounts employed.

Some single dosage forms contain both meloxicam and rizatriptan mayfurther contain, a cyclodextrin which may be complexed with meloxicam,and a bicarbonate. In addition, some dosage forms may contain excipientssuch as microcrystalline cellulose (e.g. about 1-20%), starch (e.g.about 1-10%), fumed silica (e.g. 0.1-10%), polyvinylpyrrolidone (e.g.about 1-10%), and/or magnesium stearate (e.g. about 0.1-10%).

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

Example 1

A bilayer tablet containing 1) an inclusion complex of SBEβCD withmeloxicam, prepared as described below, and 2) sodium bicarbonate wasprepared (SBEβCD-Meloxicam/Bicarbonate). The first layer contained aninclusion complex of 15 mg meloxicam and 100 mg SBEβCD, and 100 mg ofsodium bicarbonate. The second layer contained 40 mg of esomeprazole and400 mg of sodium bicarbonate.

A total of 20 human subjects were randomly assigned in a 1:1 ratio totreatment with the SBEβCD-Meloxicam/Bicarbonate tablets described aboveor Mobic® tablets (15 mg meloxicam), once daily for 6 days under fastingconditions.

On the first day of dosing, plasma samples were collected forconcentration analysis of meloxicam at several time points.Concentrations of meloxicam were determined using LC-MS/MS.Pharmacokinetic parameters were calculated. The results are depicted inFIG. 1.

The median T_(max) for meloxicam, the trial's primary endpoint, was 9times faster for the SBEβCD-Meloxicam/Bicarbonate tablets as compared toMobic® (0.5 hour versus 4.5 hours respectively, p<0.0001).

The SBEβCD-Meloxicam/Bicarbonate tablets also demonstrated higher meanmaximum plasma concentration (C_(max)) (p=0.0018), faster time totherapeutic plasma concentration (p<0.0001), and faster time tohalf-maximal plasma concentration (p<0.0001) as compared to Mobic®.

Meloxicam in the form of meloxicam/cyclodextrin inclusion complexes wasused in the tablets containing meloxicam and cyclodextrin. The inclusioncomplexes were formed by mixing meloxicam and cyclodextrin in an aqueouspH-adjusted solution. The pH of the solution was adjusted usingbuffering agents. The resulting soluble meloxicam/cyclodextrin inclusioncomplexes were then spray dried. This spray-dried dispersion was used inthe manufacture of the tablets containing cyclodextrin.

Example 2

A monolayer tablet containing 1) the inclusion complex of SBEβCD withmeloxicam; 2) rizatriptan; and 3) sodium bicarbonate was prepared(SBEβCD-Meloxicam/rizatriptan/Bicarbonate). The monolayer tabletcontained 20 mg of meloxicam, 10 mg of rizatriptan, and 500 mg of sodiumbicarbonate. The inclusion complex was the same as the inclusion complexof Example 1.

Dissolution testing of the tablets in acidic medium (chosen to simulategastric conditions) was performed by placing the tablets in a 0.01 N HClsolution, at an agitation rate of 75 RPM, and vessel temperature ofapproximately 37° C. The results are presented in Table 7. Results atvarious time points (0, 15, 30, 45, 60, 90, and 120 minutes) arepresented as percent (%) of meloxicam, and percent (%) of rizatriptandissolved.

TABLE 7 Dissolution Results Time-point 120 (minutes) 0 min 15 min 30 min45 min 60 min 90 min min Rizatriptan 0% 89% 102% 103% 103% 103% 103%Meloxicam 0% 79%  92%  93%  93%  93%  94%

As shown in Table 7, the dissolution results of the tablets in Example 2are very similar to the dissolution result of Example 1. Therefore, weexpect the pharmacokinetic properties, including bioavailability,T_(max), etc., of the tablets in Example 2 to be similar to thosedescribed in Example 1 and FIG. 1.

Example 3

The monolayer tablet of Example 2 was administered to six humansubjects. On the first day of dosing, plasma samples were collected forconcentration analysis of rizatriptan at several time points.Concentrations of rizatriptan and meloxicam were determined usingLC-MS/MS. Pharmacokinetic parameters were calculated. The results formeloxicam were comparable to those reported for the bilayer dosage formof Example 1. The median T_(max) of rizatriptan was 0.75 hours and themean C_(max) of rizatriptan was 20.710 ng/mL. By comparison, thereported T_(max) of the commercial rizatriptan dosage form, Maxalt®, is1.0-1.5 hours.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodin all instances as indicating both the exact values as shown and asbeing modified by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained. At the very least, and not asan attempt to limit the application of the doctrine of equivalents tothe scope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein. Accordingly, the claims include allmodifications and equivalents of the subject matter recited in theclaims as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof iscontemplated unless otherwise indicated herein or otherwise clearlycontradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

1. A method of treating migraine, comprising administering meloxicam andabout 8 mg to about 13 mg of rizatriptan, based upon the weight of therizatriptan in the free base form, to a human being who is sufferingfrom an acute attack of migraine pain or migraine aura, wherein themeloxicam and the rizatriptan are administered within about 30 minutesof one another, wherein administering the meloxicam to the human beingresults in a T_(max) of meloxicam of 110 minutes or less, and an AUC₀₋₂₄of meloxicam of about 30 μg·hr/mL to about 50 μg·hr/mL.
 2. The method ofclaim 1, wherein the rizatriptan is administered in a salt form in anamount that is a molar equivalent to about 10 mg of the rizatriptan inthe free base form.
 3. The method of claim 2, wherein the rizatriptan ispresent as rizatriptan benzoate.
 4. The method of claim 1, wherein about15 mg to about 25 mg of meloxicam is administered to the human being. 5.The method of claim 1, wherein about 20 mg of meloxicam is administeredto the human being.
 6. The method of claim 1, wherein the human beinghas a history of inadequate response to prior migraine treatments. 7.The method of claim 6, wherein the rizatriptan is administered in a saltform in an amount that is a molar equivalent to about 10 mg of therizatriptan in the free base form.
 8. The method of claim 6, whereinabout 15 mg to about 25 mg of meloxicam is administered to the humanbeing.
 9. The method of claim 7, wherein about 20 mg of meloxicam isadministered to the human being.
 10. The method of claim 1, wherein themeloxicam and the rizatriptan are administered simultaneously, andwherein two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater pain relief than thehuman being would have experienced two hours after receiving the sameamount of the meloxicam without the rizatriptan.
 11. The method of claim10, wherein the rizatriptan is administered in a salt form in an amountthat is a molar equivalent to about 10 mg of the rizatriptan in the freebase form.
 12. The method of claim 10, wherein about 15 mg to about 25mg of meloxicam is administered to the human being.
 13. The method ofclaim 11, wherein about 20 mg of meloxicam is administered to the humanbeing.
 14. The method of claim 1, wherein the meloxicam and therizatriptan are administered simultaneously, and wherein two hours afterthe meloxicam and the rizatriptan are administered, the human beingexperiences greater pain relief than the human being would haveexperienced two hours after receiving the same amount of the rizatriptanwithout the meloxicam.
 15. The method of claim 14, wherein therizatriptan is administered in a salt form in an amount that is a molarequivalent to about 10 mg of the rizatriptan in the free base form. 16.The method of claim 14, wherein about 15 mg to about 25 mg of meloxicamis administered to the human being.
 17. The method of claim 15, whereinabout 20 mg of meloxicam is administered to the human being.
 18. Themethod of claim 1, wherein the meloxicam and the rizatriptan areadministered simultaneously, and wherein two hours after the meloxicamand the rizatriptan are administered, the human being experiencesgreater relief from nausea than the human being would have experiencedtwo hours after receiving the same amount of the meloxicam without therizatriptan.
 19. The method of claim 1, wherein the meloxicam and therizatriptan are administered simultaneously, and wherein two hours afterthe meloxicam and the rizatriptan are administered, the human beingexperiences greater relief from nausea than the human being would haveexperienced two hours after receiving the same amount of the rizatriptanwithout the meloxicam.
 20. The method of claim 1, wherein the meloxicamand the rizatriptan are administered simultaneously, and wherein twohours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from vomiting than the humanbeing would have experienced two hours after receiving the same amountof the meloxicam without the rizatriptan.
 21. The method of claim 1,wherein the meloxicam and the rizatriptan are administeredsimultaneously, and wherein two hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom vomiting than the human being would have experienced two hoursafter receiving the same amount of the rizatriptan without themeloxicam.
 22. The method of claim 1, wherein the meloxicam and therizatriptan are administered simultaneously, and wherein two hours afterthe meloxicam and the rizatriptan are administered, the human beingexperiences greater relief from photophobia than the human being wouldhave experienced two hours after receiving the same amount of themeloxicam without the rizatriptan.
 23. The method of claim 1, whereinthe meloxicam and the rizatriptan are administered simultaneously, andwherein two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief fromphotophobia than the human being would have experienced two hours afterreceiving the same amount of the rizatriptan without the meloxicam. 24.The method of claim 1, wherein the meloxicam and the rizatriptan areadministered simultaneously, and wherein two hours after the meloxicamand the rizatriptan are administered, the human being experiencesgreater relief from phonophobia than the human being would haveexperienced two hours after receiving the same amount of the meloxicamwithout the rizatriptan.
 25. The method of claim 1, wherein themeloxicam and the rizatriptan are administered simultaneously, andwherein two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief fromphonophobia than the human being would have experienced two hours afterreceiving the same amount of the rizatriptan without the meloxicam.